Type III interferons (IFN) (IFN-lambda1, -lambda2, -lambda3/interleukin [IL]-29, -28A, -28B) are cytokines with type I IFN-like antiviral activities. Most cells have expressed both type I and III IFN following Toll-like receptor (TLR) stimulation or viral infection, whereas the ability of cells to respond to IFN-lambda was restricted to a specific subset of cells. It was reported that signal transduction pathway of IFN-lambda was similar to that of IFN-alpha/beta although a receptor adapted by IFN-lambda were distinct from that of IFN-alpha/beta. However, the clinical significance and the role of each IFN-lambda were unclear. Recent genome-wide association studies (GWAS) of the human whole genome revealed several single nucleotide polymorphism sites (SNP) strongly associated with the response to pegylated IFN-alpha (PEG-IFN) plus ribavirin (RBV) treatment in chronic hepatitis C patients. The SNP, which are located near the IL-28B gene of chromosome 19, were discovered simultaneously by three independent studies opening a new prospective in hepatitis C research. The present review highlights significant insights that can be derived from the GWAS approach, and summarizes current knowledge of in vitro and in vivo study on the role of IFN-lambda in antiviral effect.